Serum and glucocorticoid-inducible kinase1 (SGK1) is a serine-threonine kinase which was identified by Webster et al. through a differential expression screen of the glucocorticoid-induced rat mammary tumor cell. When the cell was stimulated by glucocorticoid or serum, the transcription level of SGK1 was rapidly elevated within 30 min. It is thus referred to as serum and glucocorticoid-inducible kinase. SKG1 shares high homology with second messengers such as protein kinase B (PKB/Akt). In addition to the phosphorylation and dephosphorylation regulation mechanism as similar to most protein kinases, SGK1 is also regulated in rapid transcript phase. According to reports in the literature, SGK1 is regulated by a plurality of hormones and growth factors, such as glucocorticoid, serum, mineralocorticoid, polypeptide hormone CRH and the like, which can rapidly induce the expression of SGK1. More and more studies indicate that SGK1 is a functional intersection between a plurality of cellular signal transduction pathways and cellular phosphorylation cascade, which involves with a variety of physiological functions such as signal transduction of regulation of ion channel, cell survival, differentiation, proliferation and apoptosis, and the like. Recent work has found that it is closely related to cerebral degenerative disease such as cerebral ischemia, epilepsy, Alzheimer's disease (AD), Parkinson's disease (PD), brain tumor, and the like. It plays an important role in central nervous system development, neuronal degeneration and apoptosis, and the occurrence and development of brain tumors. Abnormal increases in the expression and activity of SGK1 are involved in the development and progression of various diseases, and inhibitors of SGK1 are considered to be potential drugs for the treatment of these diseases.
The c-Jun N-terminal kinase (JNK) family is one of the members of the mitogen-activated protein kinase (MAPK) superfamily discovered in 1990, and is evolutionarily conserved serine/threonine protein kinase. The JNK signaling pathway is activated by various factors such as cytokines, growth factors, stress and the like, and plays a predominant role in cell regulation such as cell proliferation and differentiation, cell apoptosis and stress response. Dysfunction of JNK signaling pathway may result in various diseases such as ischemia-reperfusion injury, chronic inflammation, neurodegeneration, diabetes, tumors and the like. Recent studies have found that the over-activated JNK signaling pathway is closely related to Alzheimer's disease and Parkinson's disease, while knockout of JNK or JNK inhibitors can ameliorate the symptoms of AD and PD disease models. Certain studies have discovered that overexpression of JNK was shown in patients suffering from glioma, and the expression level of JUK is highly related to the grade malignancy of glioma and prognosis of the patients suffering from glioma. In addition, JNK inhibitors have been found to suppress the self-renewal capacity of glioma stem cells and to promote the differentiation of glioma stem cells into glia-like or neuron-like cells which are not tumorigenic. Therefore, JNK inhibitors are considered to be potential drugs for diseases such as neurodegenerative disease and brain tumor.
Lipoic acid (LA) is one of the most powerful natural antioxidants and known as the universal antioxidant. It is a cofactor for pyruvate dehydrogenase, and also a metabolism antioxidant. In the organism, LA can be transformed into the reduced dihydrolipoic acid (DHLA). Antioxidant effect can be obtained by scavenging free radicals and reactive oxygen, chelating metal ion and interacting with other antioxidants. Lipoic acid has the characteristics of low molecular weight and amphiphilicity, which make it easy to penetrate the blood-brain barrier, such that it can exert anti-oxidation effect in the central nervous system. Therefore, it is considered to be an effective way to treat neurodegenerative diseases. However, lipoic acid is not stable enough in the body, and is simply single targeted. LA with single anti-oxidation effect is difficult to be used alone in CNS diseases with complicated pathogenesis. Clinically, it is mainly used in combination with other drugs, or used as a pharmacophore for multi-target drug development.
As describe above, both SGK1 and JNK are highly expressed in diseases such as degenerative diseases of central nervous system or brain tumor. The suppression of SGK1 or JNK would improve the progress of diseases (such as degenerative diseases of central nervous system, brain tumor and the like) to some extent. The antioxidants also play a positive role in the treatment of the degenerative diseases of central nervous system. Complex diseases (such as degenerative diseases of central nervous system, tumors and the like) with a complicated pathogenesis and pathogenic factors interacted with each other is difficult to be treated or improved by a single drug. With the development of system biology and network pharmacology, multi-target drugs that can simultaneously act on multiple targets associated with pathogenesis is increasingly expected to be applied to the treatment of such diseases. On this basis, the present invention aims to develop a small molecule compound having dual inhibition of SGK1 and JNK and an anti-oxidation effect, thereby obtaining additive or synergistic effects in the treatment of diseases such as degenerative diseases of central nervous system and brain tumor. At the same time it can reduce inconvenience of drug combination, drug-drug interaction and other adverse factors.